Systemic lupus erythematosus (SLE) is a chronic, multisystem autoimmune disorder of unknown etiology. Recently, our understanding of the genetics of SLE increased dramatically with the use of genome-wide association analyses to identify genetic variants that are associated with disease risk in humans. The results of these studies have not only confirmed existing susceptibility genes but have also identified several new candidate genes. One of these new genetic loci is a promoter region allele that results in a reduction (i.e., 25 to 50% decrease depending on whether individuals are heterozygous or homozygous for the allele) in BLK gene expression. BLK encodes for B lymphoid kinase, a Src family tyrosine kinase, which is expressed in immature and mature human B cells and is a component of the B cell antigen receptor (BCR) signaling pathway. In this grant proposal, we plan to capitalize on this finding and develop an experimental mouse model system, in which Blk expression levels are reduced to levels comparable to those in individuals homozygous for the risk allele, to determine the mechanism(s) by which a reduction in BLK confers susceptibility to SLE. There are three key steps in the development of systemic autoimmunity, commencing with loss of tolerance to self antigens, progressing to dysregulation of both the innate and adaptive immune systems, and ending with inflammation and tissue damage. Because Blk is involved in BCR signaling and because defects in BCR signaling can result in aberrant B cell selection, we hypothesize that reduced levels of Blk lead to defects in B cell tolerance. To test our hypothesis, we will use several established mouse models to determine 1) whether reducing Blk levels alone leads to a breach in immune tolerance and 2) whether reducing Blk levels in combination with the expression of other susceptibility loci accelerates disease progression and/or exacerbates disease pathology. We anticipate that the proposed study will elucidate the functional significance of reduced levels of BLK on the development of SLE. Also, as immunological dysfunction precedes disease onset in humans by many years, this study may lead to new tests for early diagnosis and to new therapies for SLE.